About this Author

College chemistry, 1983

The 2002 Model

After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases.
To contact Derek email him directly: derekb.lowe@gmail.com
Twitter: Dereklowe

May 5, 2009

Farewell to ACAT, and to Lots of Time and Money, Too

Posted by Derek

Back when I joined the first drug company I ever worked for, the group in the lab next door was working on an enzyme called ACAT, acyl CoA:cholesterol acyltranferase. It’s the main producer of cholesterol esters in cells, and is especially known to be active in the production of foam cells in atherosclerosis. It had already been a drug target for some years before I first heard about it, and has remained one.

It hasn’t been an easy ride. Since 1990, severalcompounds have failed in the clinic or in preclinical tox testing. The most recent disappointment was in 2006, when pactimibe (Daiichi Sankyo) not only failed to perform against placebo, but actually made things slightly worse.

Lipid handling is a tough field, because every animal does is slightly differently. There are all sorts of rabbit strains and hamster models and transgenic mice, but you're never really sure until you get to humans. Complicating the story has been the discovery that there are two ACATs. ACAT-1 is found in macrophages (and the foam cells that they turn into) and many other tissues, and ACAT-2 is found in the intestine and in the liver. Which one to inhibit is a good question - the first might have a direct effect on altherosclerotic plaque formation, while the second could affect general circulating lipid levels. Pactimibe hits both about equally, as it turns out.

Now a second study of that drug has been published this spring. This one was going on at the same time as the earlier reported one, and was stopped when those results hit, but the data were in good enough shape to be worked up, and the company paid for the continued analysis. The new results look at patients with familial hypercholesterolemia, who got pactimibe along with the standard therapies. Unfortunately, the numbers are of a piece with the earlier ones: the drug did not help, and actually seemed to increase arterial wall thickness. I think it's safe to say, barring some big pharmacological revelation, that ACAT inhibitors are a dead end for atherosclerosis.

I bring this up for two reasons. One is that the group that was working next door to me on ACAT was the same group that discovered (quite by accident) the cholesterol absorption inhibitor ezetimibe, known as Zetia (and as half of Vytorin). Although its future is very much in doubt, it's for sure that that compound has been a lot more successful than any ACAT inhibitor. The arguing goes on about how helpful it's been (and will go on until we see the next trial results for another couple of years), but it's already made it further than ACAT.

And that's actually my second point. I suspect that almost no one in the general public has ever heard of ACAT at all. But it's been the subject of a huge amount of research, of time and work and money. And while we've learned more about lipid handling in humans, which is always valuable, the whole effort has been an utter loss as far as any financial return. I have no good way of estimating the direct costs (and even worse, the opportunity costs) involved with this target, but they surely add up to One Hell Of A Lot Of Money. Which is gone, and gone with hardly a sound outside the world of drug development. And this happens all the time.

Those points are two of the things that make failure so interesting. You can stumble upon 'derivative successes,'(Zetia). Meanwhile spectacular, large scale failures (to the tune of One Hell Of A Lot Of Money!)often the cost of doing do business for large scale successes.

"I have no good way of estimating the direct costs (and even worse, the opportunity costs) involved with this target, but they surely add up to One Hell Of A Lot Of Money. Which is gone, and gone with hardly a sound outside the world of drug development. And this happens all the time."

Pharma Exec sez: "Well, clearly, you should stop that from happening."

Derek although you bring out two excellent highlights of the nature of Pharma/Science research, Serendipity role and Dry Hole Risks, there is a third Gem in this post that do think most public is not attuned to: When a study is halted the work often does not get published.

You say "This one was going on at the same time as the earlier reported one, and was stopped when those results hit, but the data were in good enough shape to be worked up, and the company paid for the continued analysis" which correctly tells the general basis why most "failed work" does not get published. Often the clinical data is incomplete or has not been QC'd/verified if a trial is halted early and could take a significant amount of work/expense to do gather then do analysis and otherwise get in shape so could be publishable. In industry when a project/compound dies it is extremely hard to get any resources to do additional work just so one can generate a paper. Some out there ascribe sinister motives as attempts to "hide negative information" and unfortunately there are instances where that has happen. However this ignores circumstances that all trial safety data is provided to the FDA is some form regardless if the study is completed. Further in Science it is atypical that unsuccessful experiments get much attention, unless perhaps as a footnote or one off paragraph/slide mention when presenting stuff that did work out. It's part of the frustration in dealing with R&D in that much of what gets learned on what not to do does not end up being passed along directly in literature and only through experience and word of mouth may get disseminated.

The problem is usually that we don't have any idea what we know and don't know, so it's hard to fail fast. (It's like something lost - it's always in the last place you looked. Having management ask, "Why didn't you look there first?" probably only deserves a "Well, why didn't you tell me to look there first (if it was so damn obvious)?" There is so much that we don't know that it's likely to be hard to even guess what targets might be productive. If you knew what targets to aim for, someone else probably already has targeted them and is working on them.

Lucky you. You have a drug spammer (family) of your very own. (soon-to-be-ex-NUM 4).

Do you still believe that lipid transport had anything to do with atherosclerosis other than in a side role building plaque?

Tell me something- why do autopsies of 20-30 year old killed in war or accidents often reveal plaques but are not associated with MI. Have you considered the possibility that the body might lose it's ability to repair underlying tissue and diassemble plaques safely? Or maybe the changes that come along with hyperinsulinemia might affect those mechanisms?

I really agree here. I've even heard of a few cases when the work is published and missing from the substrate tables are the analogs you really desire. So you go head and try it only to never be sucessful. So you write the author and they respond, oh yeah well we never got any product out of that one. Unfortunately I think this kind of omission will continue until a high impact value "Journal of Suff That Never Really Worked"

I'll offer to send you five bucks if you can offer proof of your assertion in the form of a study that's less than 20 years old and widely believed to be valid. Hell, I'll even leave it up to Derek's commenters to judge whether or not it's valid.

What about discovering a drug that reduces MI by altering serum lipids (a large study)?

But I forgot.. The vast majority of scientists employed in drug companies have their current jobs through pedigree and networking. They could not invent themselves out of a paper bag if their life depended on it. I always find it funny that people who have never involved in the discovery of even one innovative drug consider themselves as the gatekeepers of the "drug discovery process" and like to tell you that they understand the problem.

I would suggest that you hold on to your five bucks because at the rate pharma is "consolidating", you might need it.. real soon.

Lucifer: apparently p38 alpha has a protective role and prevents macrophage necrosis inside the plaque - disrupting that signal produces fragile atherosclerosis-like plaques in animal model. Its actually the accumulation of dead cells inside the plaque that differentiates the plaques that can rupture from those that do not. And the macrophages are prone to necrosis once they engorge themselves on cholesterol inside the plaque...

Your statement, "The vast majority of scientists employed in drug companies have their current jobs through pedigree and networking" does not apply to 99% of the scientist I have worked with, though it is sometimes true. However, where true, it was in the management chain of a newly hired academic wunderkind that brought along friends and colleagues. The "vast majority" are in industry to do good by contributing to discovery and development of meaningful meds. Pedigree is best left in academia, IMO.

Hey, Lucifer -- I'm calling you out again. Show me proof of your assertion that "autopsies of 20-30 year old killed in war or accidents often reveal plaques but are not associated with MI". A link or a cite will do just fine.

Your appeal to authority is truly excellent, BTW.

Shut me up, buddy -- I'll even pay you five bucks if you can find a peer-reviewed study where this assertion is made.